Nitrogen-containing heterocycles such as pyrimidine derivatives have been disclosed in patent and non-patent publications as having a variety of pharmaceutical properties and utilities. Several such publications are listed below.
WO 03/062225 (Bayer) relates to pyrimidine derivatives as rho-kinase inhibitors, and their use in treatment of rho-kinase mediated conditions including cancer.
WO 2001/87845 (Fujisawa) relates to N-containing heterocyclic compounds having 5-HT antagonistic activity. These compounds are stated as being useful for treating or preventing central nervous system disorders.
WO 95/10506 (Du Pont Merck) relates to 1N-alkyl-N-arylpyrimidinamines and derivatives thereof, which are stated to inhibit the corticopropin releasing factor (CRF) peptide and to be useful for treatment of psychiatric disorders and neurological diseases.
WO 2004/048365 (Chiron) relates to 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (PI) 3-kinase inhibitors and their use in treatment of cancer.
WO 2004/000820 (Cellular Genomics) relates to N-containing heterocycles and other compounds as kinase modulators, and their use in treatment of numerous kinase-associated disorders including cancer.
WO 01/62233 (Hoffmann La Roche) relates to nitrogen-containing heterocycles and their use in treatment of diseases modulated by the adenosine receptor.
U.S. 2004/0097504 (Vertex) relates to nitrogen-containing heterocycles useful in treatment of various protein kinase-mediated disorders.
The pharmaceutical field is always interested in identifying new pharmaceutically active compounds. Such materials are the subject of the present application.
Compounds of the Invention
In a first embodiment, this invention relates to compounds of Formula (I)

wherein    R1 represents H, (C1-C3)alkyl, or cyclopropyl;    R2 represents (C1-C3)alkyl, cyclopropyl, O(C1-C3)alkyl, or NR3R4             wherein R3 and R4 are H, (C1-C3)alkyl, or cyclopropyl;            R2a represents H or halogen;    M represents CH or N;    L represents a carbonyl group, O, NR5, CR6R7, or (C2-C3)alkylenyl which is optionally substituted up to twice by groups independently selected from halogen and OH; wherein            R5 is H or (C1-C3)alkyl; and        R6 and R7 are independently H, CH3, halogen, or OH;            J represents an aromatic or heteroaromatic ring selected from the group consisting of
    Y represents an aromatic or heteroaromatic ring selected from the group consisting of
                wherein R8 represents H or (C1-C3)alkyl;            G″ represents a substituent selected from the group consisting of (C1-C3)alkyl, cyclopropyl, O(C1-C3)alkyl, halogen, CF3, CN and CO2R9;            wherein        R9 represents H or (C1-C3)alkyl, and            m represents the number of substituents G″, and is 0, 1, or 2;    G represents a substituent located on ring J;    G′ represents a substituent located on ring Y;    n represents the number of substituents G; and    n′ represents the number of substituents G′;    n and n′ are independently 0, 1, 2, or 3, subject to the provisos that            1) ring J and ring Y each may be substituted independently up to 3 times by substituents listed below as numbers G1-G2, to a maximum total of 4 substituents on rings J and Y,        2) ring J and ring Y each may be substituted independently up to 2 times by substituents listed below as numbers G3-G01, to a maximum total of 3 substituents on rings J and Y, and        3) ring J and ring Y each may be substituted independently once by a substituent selected from those listed below as numbers G12-G37;and subject to the further provisos        4) when J is phenyl, G is other than OH or alkylthio; and when J is phenyl or pyridyl, n is 1, 2, or 3;        5) when J is phenyl, and G is G4 shown below, then R2 is NR3R4;            G and G′ moieties are independently selected from the group consisting of:            G1) halogen;        G2) O(C1-C4)alkyl which optionally is substituted up to two times by O(C1-C2)alkyl;        G3) OH;        G4) (C1-C5)alkyl, which is optionally substituted independently up to two times by groups selected from hydroxyl and cyano, or up to three times by halogen;        G5) OCF3;        G6) NHC(O)(C1-C3)alkyl;        G7) NHSO2(C1-C3)alkyl;        G8) NR10R11, wherein                    R10 and R11 are independently selected from            H,            CH3,            cyclopropyl,            benzyl,            NR12R13 wherein                            R12 and R13 are independently H or (C1-C3)alkyl, provided that both R10 and R11 are not NR12R13 simultaneously, and                                    (C2-C4)alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C1-C3)alkyl, and NR14R15, wherein                            R14 and R15 are independently H or (C1-C3)alkyl, or                                     R14 and R15 can join to form a heterocycle of formula                        
                                     wherein                            Q represents CH2, O, or NR16, and                R16represents H or (C1-C3)alkyl, or                                                 R10 and R11 may be joined to form a saturated 5-6-membered N-containing ring which is optionally substituted up to two times by OH,                    NR17R18, wherein                            R17 and R18 are H or (C1-C3)alkyl, or by                                    (C1-C3)alkyl which is optionally substituted up to two times by halogen, OH, or O(C1-C3)alkyl;                        G9) (CH2)a—NR19R20 wherein                    R19 and R20 are independently H, (C1-C5)alkyl, or (C3-C6)cycloalkyl, or may be joined to form a saturated 5-6-membered N-containing ring; and            the subscript “a” is an integer of 1-4;                        
                                     wherein            Q′ is O or NR21;            R21 is H, (C1-C3)alkyl, or cyclopropyl; and            the subscript “b” is an integer of 1-3;                        G11) CH2NR22(CH2)cOCH3 wherein                    R22 is H, (C1-C3)alkyl, or cyclopropyl; and            the subscript “c” is an integer of 2-4;                        G12) OSO2NR23R24 wherein                    R23 and R24 independently represent H, CH3, or (C2-C4)alkyl which may optionally be substituted once by OH or NR25R26, wherein                            R25 and R26 independently represent H or (C1-C3)alkyl;                                                G13) CN;        G14) NO2;        G15) cyclopropyl;        G16) OR27, wherein                    R27 represents phenyl or benzyl;                        G17) S(C1-C3)alkyl;        G18) CH═CH—(CH2)1-3—OR5; wherein                    R5 represents H or (C1-C3)alkyl;                        
                G21) C(O)NR28R29, wherein                    R28 and R29 are independently selected from H,            cyclopropyl, provided that both R28 and R29 are not simultaneously cyclopropyl,                        
                                     provided that this group does not constitute both R28 and R29 simultaneously, and            (C1-C3)alkyl which is optionally substituted up to two times by OH; or            R28 and R29 may be joined to form a saturated 5-6-membered N-containing ring which is optionally substituted up to two times by OH, or by (C1-C3)alkyl which in turn is optionally substituted up to two times by OH or O(C1-C3)alkyl;                        
                 wherein                    Q″ is O or NR30, and            R30 is H, cyclopropyl, or                            (C1-C3)alkyl which is optionally substituted once by halogen, OH, or O(C1-C3)alkyl;                                                G23) O—(CH2)d—NR31R32 wherein                    R31 and R32 are independently H, (C1-C3)alkyl, or cyclopropyl, or may be joined to form a saturated 5-6-membered N-containing ring; and            the subscript “d” is an integer of 2-4;                        
                                     wherein            the subscript “e” is an integer of 2-3; and            Q′″ is O or NR33; and            R33 is H, (C1-C3)alkyl, or cyclopropyl;                        
                                     wherein            Qiv is O or NR34; and            R34 is H, (C1-C3)alkyl, or cyclopropyl;                        G26) C(O)NR35(CH2)fOR36 wherein                    R35 is H, (C1-C3)alkyl, or cyclopropyl;            R36 is (C1-C6)alkyl optionally substituted up to two times by halogen, OH, or O(C1-C3)alkyl, and            the subscript “f” is an integer of 2-4;                        G27) CO2R37 wherein                    R37 is H or (C1-C3)alkyl;                        G28) phenyl, which is optionally substituted by up to 2 groups selected from halogen, (C1-C3)alkyl, OR38, CN, CF3, and NR39R40 wherein                    R38 represents H or (C1-C3)alkyl; and            R39 and R40 represent H or (C1-C3)alkyl;                        G29) NR41SO2NR42R43 wherein                    R41represents H, or (C1-C4)alkyl, and            R42 and R43 independently represent H, CH3, or (C2-C3)alkyl which may optionally be substituted once by —OH or NR44R45, wherein                            R44 and R45 independently represent H or (C1-C3)alkyl;                                                G30) OC(O)—CH2—NR46R47 wherein                    R46 and R47 independently represent H, (C1-C3)alkyl, or CO2(t-butyl), provided that R46 and R47 are not both simultaneously CO2(t-butyl);                        G31) N(R48)C(O)R49 wherein                    R48 represents H or (C1-C3)alkyl; and            R49 represents                            (CH2)1-3—CO2H,                O(C2-C4)alkyl,                (CH2)1-4—NR50R51 wherein                                    R50 and R51 independently represent H or (C1-C3)alkyl, or                                                CH(R52)—NR53R54 wherein                                    R52 represents (CH2)1-4—NH2, CH2OH, CH(CH3)OH, or (C1-C3)alkyl; and                    R53 and R54 independently represent H or (C1-C3)alkyl;                                                                                G32) C(O)—(C1-C3)alkyl;        G33) (CH2)g—N(R55)—C(O)—R56 wherein                    g represents 1, 2, or 3;            R55 represents H or (C1-C3)alkyl;            R56 represents                            (C1-C3)alkyl optionally substituted up to two times by OR57 or NR58R59, wherein                                    R57 represents H or (C1-C3)alkyl, and                    R58 and R59 each represents H or (C1-C3)alkyl,                                                                    or R56 represents                        
                                     wherein                            R60 represents halogen, (C1-C3)alkyl, O(C1-C3)alkyl, CN, OH, CF3, or NR61R62, wherein                                    R61 and R62 represent H or (C1-C3)alkyl; and                                                h represents 0, 1, or 2;                                                G34) (CH2)i—N(R63)—C(O)—NR64R65 wherein                    i represents 1, 2, or 3;            R63 represents H or (C1-C3)alkyl;            R64 and R65 each represents H or (C1-C3)alkyl; or            R64 and R65 may be joined to form                        
                                     wherein                            QV represents CH2, O or NR66 wherein                                    R66 represents H or (C1-C3)alkyl;                                                                                
                                                                                                     wherein                                                                    j represents 1, 2, or 3;            R67represents H or (C1-C3)alkyl; and            R68 represents H or (C1-C3)alkyl;                        G36) (CH2)k—N(R69)—SO2—R70 wherein                    k represents 1, 2, or 3;            R69 represents H or (C1-C3)alkyl; and            R70 represents (C1-C4)alkyl, or phenyl which is optionally substituted up to perhalo by halogen or up to three times by OR71, CN, CF3, or NR72R73, wherein                            R71 represents H or (C1-C3)alkyl; and                R72 and R73 each represents H or (C1-C3)alkyl;                                                G37) CH═CH—(CH2)1-3—NR74R75 wherein                    R74 and R75 represent H or (C1-C3)alkyl;or a pharmaceutically acceptable salt, solvate, solvate of a salt, or stereoisomer thereof.                        
In a second embodiment, the invention relates to a compound of the above first embodiment, having the structure
wherein the definitions of the variables are as given above in the first embodiment, except that in this second embodiment    R1 represents H;    M represents CH;    J represents a heteroaromatic ring selected from the group consisting of
    Y represents an aromatic or heteroaromatic ring selected from the group consisting of
    n and n′ are independently 0, 1, 2, or 3, subject to the provisos that            1) ring J and ring Y each may be substituted independently up to 3 times by substituents listed below as numbers G1-G2, to a maximum total of 4 substituents on rings J and Y,        2) ring J and ring Y each may be substituted independently up to 2 times by substituents listed below as numbers G3-G5 and G8, to a maximum total of 3 substituents on rings J and Y, and        3) ring J and ring Y each may be substituted independently once by a substituent selected from those listed below as numbers G12, G13, G22, G29, and G31;and subject to the further proviso        4) when J is pyridyl, n is 1, 2, or 3;and proviso 5 does not apply;            G and G′ moieties are independently selected from the group consisting of:            G1) halogen;        G2) O(C1-C4)alkyl which optionally is substituted up to two times by O(C1-C2)alkyl;        G3) OH;        G4) (C1-C5)alkyl, which is optionally substituted independently up to two times by groups selected from hydroxyl and cyano, or up to three times by halogen;        G5) OCF3;        G8) NR10R11, wherein                    R10 and R11 are independently selected from H, CH3, cyclopropyl, benzyl, NR12R13 wherein                                                                R12 and R13 are independently H or (C1-C3)alkyl, provided that both R10 and R11 are not NR12R13 simultaneously, and                                                (C2-C4)alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C1-C3)alkyl, and NR14R15, wherein                                    R14 and R15 are independently H or (C1-C3)alkyl, or                    R14 and R15 can join to form a heterocycle of formula                                                                                
                                                                                                     wherein                     Q represents CH2, O, or NR16, and                     R16 represents H or (C1-C3)alkyl,                                                or                                    R10 and R11 may be joined to form a saturated 5-6-membered N-containing ring which is optionally substituted up to two times by OH,                            NR17R18, wherein                                    R17 and R18 are H or (C1-C3)alkyl, or by                                                (C1-C3)alkyl which is optionally substituted up to two times by halogen, OH, or O(C1-C3)alkyl;                                                G12) OSO2NR23R24 wherein                    R23 and R24 independently represent H, CH3, or (C2-C4)alkyl which may optionally be substituted once by OH or NR25R26, wherein                            R25 and R26 independently represent H or (C1-C3)alkyl;                                                G13) CN;        
                 wherein                    Q″ is O or NR30, and            R30 is                            H,                cyclopropyl, or                (C1-C3)alkyl which is optionally substituted once by halogen, OH, or O(C1-C3)alkyl;                                                G29) NR41SO2NR42R43 wherein                    R41represents H, or (C1-C4)alkyl, and            R42 and R43 independently represent H, CH3, or (C2-C3)alkyl which may optionally be substituted once by —OH or NR44R45, wherein                            R44 and R45 independently represent H or (C1-C3)alkyl; and                                                G31) N(R48)C(O)R49 wherein                    R48 represents H or (C1-C3)alkyl; and            R49 represents                            (CH2)1-3—CO2H,                O(C2-C4)alkyl,                (CH2)1-4—NR50R51 wherein                                    R50 and R51 independently represent H or (C1-C3)alkyl, or                                                CH(R12)—NR53R54 wherein                                    R52 represents (CH2)1-4—NH2, CH2OH, CH(CH3)OH, or (C1-C3)alkyl; and                    R53 and R54 independently represent H or (C1-C3)alkyl.In a third embodiment the invention relates to a compound of the above second embodiment, having the structure                                                                                
wherein the definitions of the variables are as given above in the second embodiment, except that in this third embodiment    R1 represents H;    R2 represents O(C1-C3)alkyl or NR3R4             wherein R3 and R4 are H or (C1-C3)alkyl;            R2a represents H;    L represents O or CR6R7 wherein            R6 and R7 are independently H, CH3, or OH;            G″ represents a substituent selected from the group consisting of O(C1-C3)alkyl, halogen, and CF3;    n and n′ are independently 0 or 1, and provisos 1-3 do not apply,    G and G′ moieties are independently selected from the group consisting of:            G1) Cl or F;        G2) O(C1-C3)alkyl;        G3) OH;        G4) (C1-C3)alkyl, which is optionally substituted up to three times by halogen;        G5) OCF3;        G8) NR10R11, wherein                    R10 and R11 are independently selected from                            H,                CH3,                cyclopropyl,                benzyl,                NR12R13 wherein                                    R12 and R13 are independently H or (C1-C3)alkyl, provided that both R10 and R11 are not NR12R13 simultaneously,                                                and                (C2-C4)alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C1-C3)alkyl, and NR14R15, wherein                                    R14 and R15 are independently H or (C1-C3)alkyl, or                    R14 and R15 can join to form a heterocycle of formula                                                                                
                                                                                                     wherein                     Q represents CH2, O, or NR16, and                     R16represents H or (C1-C3)alkyl,                                                                                G12) OSO2NR23R24 wherein                    R23 and R24 independently represent H, CH3, or (C2-C4)alkyl which may optionally be substituted once by OH or NR25R26 wherein                            R25 and R26 independently represent H or (C1-C3)alkyl;                                                G13) CN;        
                wherein                    Q″ is O or NR30, and            R30 is H or (C1-C3)alkyl; and                        G31) N(R48)C(O)R49 wherein                    R48 represents H or (C1-C3)alkyl; and            R49 represents                            (CH2)1-3—CO2H,                O(C2-C4)alkyl,                (CH2)1-4—NR50R51 wherein                                    R50 and R51 independently represent H or (C1-C3)alkyl, or                                                CH(R52)—NR53R54 wherein                                    R52 represents (CH2)1-4—NH2, CH2OH, CH(CH3)OH, or (C1-C3)alkyl; and                    R53 and R54 independently represent H or (C1-C3)alkyl.                                                                                
In a fourth embodiment, the invention relates to a compound of the above first embodiment, having the structure
wherein the definitions of the variables are as given above in the first embodiment, except that in this fourth embodiment    R1 represents H;    M represents CH;    J represents a heteroaromatic ring selected from the group consisting of
    Y represents an aromatic or heteroaromatic ring selected from the group consisting of
    n and n′ are independently 0, 1, 2, or 3, subject to the provisos that            1) ring J and ring Y each may be substituted independently up to 3 times by substituents listed below as numbers G1-G2, to a maximum total of 4 substituents on rings 3 and Y,        2) ring J and ring Y each may be substituted independently up to 2 times by substituents listed below as numbers G3-G5 and G8, to a maximum total of 3 substituents on rings J and Y, and        3) ring J and ring Y each may be substituted independently once by a substituent selected from those listed below as numbers G12, G21, G25, G26, and G31;and subject to the further proviso        4) when J is pyridyl, n is 1, 2, or 3;and proviso 5 does not apply;            G and G′ moieties are independently selected from the group consisting of:            G1) halogen;        G2) O(C1-C4)alkyl which optionally is substituted up to two times by O(C1-C2)alkyl;        G3) OH;        G4) (C1-C5)alkyl, which is optionally substituted independently up to two times by groups selected from hydroxyl and cyano, or up to three times by halogen;        G5) OCF3;        G8) NR10R11, wherein                    R10 and R11 are independently selected from                            H,                CH3,                cyclopropyl,                benzyl,                NR12R13 wherein                                    R12 and R13 are independently H or (C1-C3)alkyl, provided that both R10 and R11 are not NR12R13 simultaneously,                                                and                (C2-C4)alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C1-C3)alkyl, and NR14R15, wherein                                    R14 and R15 are independently H or (C1-C3)alkyl, or                    R14 and R15 can join to form a heterocycle of formula                                                                                
                                                                                                     wherein                     Q represents CH2, O, or NR16, and                     R16represents H or (C1-C3)alkyl,                                                or                                    R10 and R11 may be joined to form a saturated 5-6-membered N-containing ring which is optionally substituted up to two times by                            OH,                NR17R18, wherein                                    R17 and R18 are H or (C1-C3)alkyl,                                                or by                (C1-C3)alkyl which is optionally substituted up to two times by halogen, OH, or O(C1-C3)alkyl;                                                G12) OSO2NR23R24 wherein                    R23 and R24 independently represent H, CH3, or (C2-C4)alkyl which may optionally be substituted once by OH or NR25R26 wherein                            R25 and R26 independently represent H or (C1-C3)alkyl;                                                G21) C(O)NR28R29, wherein                    R28 and R29 are independently selected from                            H,                cyclopropyl, provided that both R28 and R29 are not simultaneously cyclopropyl,                                                
                                                                 provided that this group does not constitute both R28 and R29 simultaneously,                and                (C1-C3)alkyl which is optionally substituted up to two times by OH;                or                R28 and R29 may be joined to form a saturated 5-6-membered N-containing ring which is optionally substituted up to two times by OH, or by (C1-C3)alkyl which in turn is optionally substituted up to two times by OH or O(C1-C3)alkyl;                                                
                wherein                    Q″ is O or NR34; and            R34 is H, (C1-C3)alkyl, or cyclopropyl;                        G26) C(O)NR35(CH2)fOR36 wherein                    R35 is H, (C1-C3)alkyl, or cyclopropyl;            R36 is (C1-C6)alkyl optionally substituted up to two times by halogen, OH, or O(C1-C3)alkyl, and            the subscript “f” is an integer of 2-4; and                        G31) N(R48)C(O)R49 wherein                    R48 represents H or (C1-C3)alkyl; and            R49 represents                            (CH2)1-3—CO2H,                O(C2-C4)alkyl,                (CH2)1-4—NR50R51 wherein                                    R50 and R51 independently represent H or (C1-C3)alkyl, or                                                CH(R52)—NR53R54 wherein                                    R52 represents (CH2)1-4—NH2, CH2OH, CH(CH3)OH, or (C1-C3)alkyl; and                    R53 and R54 independently represent H or (C1-C3)alkyl.                                                                                
In a fifth embodiment, the invention relates to a compound of the above fourth embodiment, having the structure
wherein the definitions of the variables are as given above in the fourth embodiment, except that in this fifth embodiment    R1 represents H;    R2 represents O(C1-C3)alkyl or NR3R4             wherein R3 and R4 are H or (C1-C3)alkyl;            R2a represents H;    L represents O or CR6R7, wherein            R6 and R7 are independently H, CH3, or OH;            G″ represents a substituent selected from the group consisting of O(C1-C3)alkyl, halogen, and CF3;    n and n′ are independently 0 or 1, and provisos 1-3 do not apply;    G and G′ moieties are independently selected from the group consisting of:            G1) Cl or F;        G2) O(C1-C3)alkyl;        G3) OH;        G4) (C1-C3)alkyl, which is optionally substituted up to three times by halogen;        G5) OCF3;        G8) NR10R11, wherein                    R10 and R11 are independently selected from                            H,                CH3,                cyclopropyl,                benzyl,                NR12R13 wherein                                    R12 and R13 are independently H or (C1-C3)alkyl, provided that both R10 and R11 are not NR12R13 simultaneously,                                                and                (C2-C4)alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C1-C3)alkyl, and NR14R15, wherein                                    R14 and R15 are independently H or (C1-C3)alkyl, or                    R14 and R15 can join to form a heterocycle of formula                                                                                
                                                                                                     wherein                     Q represents CH2, O, or NR16, and                     R16represents H or (C1-C3)alkyl,                                                                                G12) OSO2NR23R24 wherein                    R23 and R24 independently represent H, CH3, or (C2-C4)alkyl which may optionally be substituted once by OH or NR25R26, wherein                            R25 and R26 independently represent H or (C1-C3)alkyl;                                                G21) C(O)NR28R29, wherein                    R28 and R29 are independently selected from                            H                and                (C1-C3)alkyl which is optionally substituted up to two times by OH;                                                
                                                                 wherein                Qiv is O or NR34; and                R34 is H or (C1-C3)alkyl;                                                G26) C(O)NR35(CH2)fOR36 wherein                    R35 is H or (C1-C3)alkyl;            R36 is (C1-C6)alkyl optionally substituted up to two times by halogen, OH, or O(C1-C3)alkyl, and            the subscript “T” is an integer of 2-4; and                        G31) N(R48)C(O)R49 wherein                    R48 represents H or (C1-C3)alkyl; and            R49 represents                            (CH2)1-3—CO2H,                O(C2-C4)alkyl,                (CH2)1-4—NR51R51 wherein                                    R50 and R51 independently represent H or (C1-C3)alkyl, or                                                CH(R52)—NR53R54 wherein                                    R52 represents (CH2)1-4—NH2, CH2OH, CH(CH3)OH, or (C1-C3)alkyl; and                    R53 and R54 independently represent H or (C1-C3)alkyl.                                                                                
In a sixth embodiment, the invention relates to a compound of the above first embodiment, having the structure
wherein the definitions of the variables are as given above in the first embodiment, except that in this sixth embodiment    R1 represents H;    M represents CH;    J represents an aromatic or heteroaromatic ring selected from the group consisting of
    Y represents an aromatic or heteroaromatic ring selected from the group consisting of
    n and n′ are independently 0, 1, 2, or 3, subject to the provisos that            1) ring J and ring Y each may be substituted independently up to 3 times by substituents listed below as numbers G1-G2, to a maximum total of 4 substituents on rings J and Y,        
2) ring J and ring Y each may be substituted independently up to 2 times by substituents listed below as numbers G3-G5 and G8, to a maximum total of 3 substituents on rings J and Y, and
3) ring J and ring Y each may be substituted independently once by a substituent selected from those listed below as numbers G12, G22, and G31;
and subject to the further proviso
                4) when J is pyridyl, n is 1, 2, or 3; and proviso 5 does not apply;            G and G′ moieties are independently-selected from the group consisting of:            G1) halogen;        G2) O(C1-C4)alkyl which optionally is substituted up to two times by        O(C1-C2)alkyl;        G3) OH;        G4) (C1-C5)alkyl, which is optionally substituted independently up to two times by groups selected from hydroxyl and cyano, or up to three times by halogen;        G5) OCF3;        G8) NR10R11, wherein                    R10 and R11 are independently selected from                            H,                CH3,                cyclopropyl,                benzyl,                NR12R13 wherein                                    R12 and R13 are independently H or (C1-C3)alkyl, provided that both R10 and R11 are not NR12R13 simultaneously,                                                and                (C2-C4)alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C1-C3)alkyl, and NR14R15, wherein                                    R14 and R15 are independently H or (C1-C3)alkyl, or                    R14 and R15 can join to form a heterocycle of formula                                                                                
                                                                                                     wherein                     Q represents CH2, O, or NR16, and                     R16represents H or (C1-C3)alkyl,                                                or                                    R10 and R11 may be joined to form a saturated 5-6-membered N-containing ring which is optionally substituted up to two times by                            OH,                NR17R18, wherein                                    R17 and R18 are H or (C1-C3)alkyl,                                                or by                (C1-C3)alkyl which is optionally substituted up to two times by halogen, OH, or O(C1-C3)alkyl;                                                G12) OSO2NR23R24 wherein                    R23 and R24 independently represent H, CH3, or (C2-C4)alkyl which may optionally be substituted once by OH or NR25R26, wherein                            R25 and R26 independently represent H or (C1-C3)alkyl;                                                
                                                                 wherein                Q″ is O or NR30, and                R30 is                                    H,                    cyclopropyl, or                    (C1-C3)alkyl which is optionally substituted once by halogen, OH, or O(C1-C3)alkyl; and                                                                                G31) N(R48)C(O)R49 wherein                    R48 represents H or (C1-C3)alkyl; and            R49 represents                            (CH2)1-3—CO2H,                O(C2-C4)alkyl,                (CH2)1-4—NR50R51 wherein                                    R50 and R51 independently represent H or (C1-C3)alkyl, or                                                CH(R52)—NR53R54 wherein                                    R52 represents (CH2)1-4—NH2, CH2OH, CH(CH3)OH, or (C1-C3)alkyl; and                    R53 and R54 independently represent H or (C1-C3)alkyl.                                                                                
In a seventh embodiment, the invention relates to a compound of the above sixth embodiment, having the structure
wherein the definitions of the variables are as given above in the sixth embodiment, except that in this seventh embodiment    R1 represents H;    R2 represents O(C1-C3)alkyl, or NR3R4             wherein R3 and R4 are H or (C1-C3)alkyl;            R2a represents H;    L represents O or CR6R7, wherein            R6 and R7 are independently H, CH3, or OH;            G″ represents a substituent selected from the group consisting of O(C1-C3)alkyl, halogen, and CF3;    n and n′ are independently 0 or 1, and provisos 1-3 do not apply;    G and G′ moieties are independently selected from the group consisting of:            G1) Cl or F;        G2) O(C1-C3)alkyl;        G3) OH;        G4) (C1-C3)alkyl, which is optionally substituted up to three times by halogen;        G5) OCF3;        G8) NR10R11, wherein                    R10 and R11 are independently selected from                            H,                CH3,                cyclopropyl,                benzyl,                NR12R13 wherein                                    R12 and R13 are independently H or (C1-C3)alkyl, provided that both R10 and R11 are not NR12R13 simultaneously,                                                and                (C2-C4)alkyl which is optionally substituted up to three times by halogen, and up to two times by substituent groups independently selected from hydroxyl, O(C1-C3)alkyl, and NR14R15, wherein                                    R14 and R15 are independently H or (C1-C3)alkyl, or                    R14 and R15 can join to form a heterocycle of formula                                                                                
                                                                                                     wherein                     Q represents CH2, O, or NR16, and                     R16represents H or (C1-C3)alkyl;                                                                                G12) OSO2NR23R24 wherein                    R23 and R24 independently represent H, CH3, or (C2-C4)alkyl which may optionally be substituted once by OH or NR25R26 wherein                            R25 and R26 independently represent H or (C1-C3)alkyl;                                                
                                                                 wherein                Q″ is O or NR30, and                R30 is H or (C1-C3)alkyl; and                                                G331) N(R48)C(O)R49 wherein                    R48 represents H or (C1-C3)alkyl; and            R49 represents                            (CH2)1-3—CO2H,                O(C2-C4)alkyl,                (CH2)1-4—NR51R51 wherein                                    R50 and R51 independently represent H or (C1-C3)alkyl, or                                                CH(R52)NR53R54 wherein                                    R52 represents (CH2)1-4—NH2, CH2OH, CH(CH3)OH, or (C1-C3)alkyl; and                    R53 and R54 independently represent H or (C1-C3)alkyl.                                                                                
Pharmaceutically acceptable salts of these compounds as well as commonly used prodrugs of these compounds such as, for example, O-acyl derivatives of invention compounds which contain hydroxy groups, ester derivatives of invention compounds which contain carboxyl groups, and amide derivatives of invention compounds which contain amino groups, are also within the scope of the invention.
It is to be understood that:
1) in compounds of the invention in which an alkyl moiety may bear substituents such as amino, hydroxyl, alkoxy, and halogen groups, a single carbon atom of this alkyl moiety may not simultaneously bear two groups independently selected from amino, hydroxyl, and alkoxy; and where this alkyl moiety bears a halogen, it may not simultaneously also bear an amino, hydroxyl, or alkoxy substituent.
2) in compounds of the invention in which any moiety is defined in terms of a numerical range of atoms and this moiety is further permitted to bear up to a certain number of substituents, if the total number of substituents possible exceeds the number of valences available for moieties at the lower end of the defined numerical range of atoms, then the number of substituents is limited to the number of available valences. For example, if a (C1-C3)alkyl moiety if defined as optionally bearing up to three halogens and up to two other defined substituents, this means that a C1-alkyl group could bear up to three substituents (the number of available valences), all of which could be halogen, but no more than two of which could be other defined substituent groups.
The compounds of Formula (I) may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration. Preferred isomers are those with the absolute configuration which produces the compound of Formula (I) with the more desirable biological activity. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two aromatic rings of the specified compounds.
It is intended that all isomers (including enantiomers and diastereomers), either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the scope of the instant invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art.
The terms identified above have the following meaning throughout:
The term “optionally substituted” means that the moiety so modified may have from none to up to at least the highest number of substituents indicated. The substituent may replace any H atom on the moiety so modified as long as the replacement is chemically possible and chemically stable. When there are two or more substituents on any moiety, each substituent is chosen independently of any other substituent and can, accordingly, be the same or different.
The term “halogen” means an atom selected from Cl, Br, F, and I.
The terms “(C1-C2)alkyl,” “(C1-C3)alkyl” “(C1-C4)alkyl” “(C1-C5)alkyl,” and “(C1-C6)alkyl” mean linear or branched saturated carbon groups having from about 1 to about 2, about 3, about 4, about 5 or about 6 C atoms, respectively. Such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, n-hexyl, and the like.
The term “alkylenyl” means a divalent linear or branched saturated carbon chain, usually having from about 1 to about 3 carbon atoms in this application. Such chains include, but are not limited to methylene (—CH2—), ethylenyl (—CH2CH2)—, and propylenyl (—CH2CH2CH2—) and the like.
The term “(C3-C6)cycloalkyl” means a saturated monocyclic alkyl group of from about 3 to about 6 carbon atoms and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Pharmaceutical Compositions
The invention also relates to pharmaceutical compositions comprising at least one of the compounds of the invention, or a salt or prodrug thereof, in a pharmaceutically acceptable carrier.
Method of Treating Hyperproliferative Disorders
The present invention also relates to a method of using the compounds described above, including salts, prodrugs, and corresponding pharmaceutical compositions thereof, to treat mammalian hyperproliferative disorders. This method comprises administering to a patient an amount of a compound of this invention, or a pharmaceutically acceptable salt or prodrug thereof, which is effective to treat the patient's hyperproliferative disorder. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for a particular hyperproliferative disorder. A pharmaceutically effective amount of a compound or composition is that amount which produces a desired result or exerts an influence on the particular hyperproliferative disorder being treated.
Hyperproliferative disorders include but are not limited to solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. These disorders also include lymphomas, sarcomas, and leukemias.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma
Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, and urethral cancers.
Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to hepatocellular carcinoma (Giver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to laryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lip and oral cavity cancer.
Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
The utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the in vitro tumor cell proliferation assay described below. The link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been well established in the art. For example, the therapeutic utility of taxol (Silvestrini; et al. Stem Cells 1993, 11(6), 528-35), taxotere (Bissery et al. Ant Cancer Drugs 1995, 6(3), 339), and topoisomerase inhibitors (Edelman et al. Cancer Chemother. Pharmacol. 1996, 37(5), 385-93) was demonstrated with the use of in vitro tumor proliferation assays.
In this application, where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.
Salts are especially the pharmaceutically acceptable salts of compounds of formula I such as, for example, acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom. Suitable inorganic acids are, for example, halogen acids such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic, or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, -hydroxybutyric acid, gluconic acid, glucosemonocarboxylic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azeiaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids, such as glutamic acid, aspartic acid, N-methylglycine, acetytaminoacetic acid, N-acetylasparagine or N-acetylcysteine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3-glycerophosphoric acid.
The compounds of the invention may be administered orally, dermally, parenterally, by injection, by inhalation or spray, or sublingually, rectally or vaginally in dosage unit formulations. The term ‘administered by injection’ includes intravenous, intraarticular, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired, other active ingredients.
Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.
Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
The compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.
Compounds of the invention may also be administered transdermally using methods known to those skilled in the art (see, for example: Chien; “Transdermal Controlled Systemic Medications”; Marcel Dekker, Inc.; 1987. Lipp et al. WO 94/04157 3 Mar. 94). For example, a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.
Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
Suitable penetration enhancing materials for transdermal delivery systems are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C8-C18 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C8-C18 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tert-butyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations may also include mixtures one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C8-C18 fatty alcohols, saturated or unsaturated C8-C18 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.
Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene copolymers, and natural and synthetic rubbers. Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.
For all regimens of use disclosed herein for compounds of Formula I, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.
It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
General Preparative Methods
The compounds of the invention have the general chemical structure shown below and may be prepared by the use of known chemical reactions and procedures. The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific J and Y moieties, as well as the specific substituents possible at various locations on the molecule, all play a role in the path to be followed in the preparation of the specific compounds of this invention. Those factors are readily recognized by one skilled in the art.
Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the compounds of the invention, with more detailed particular examples being presented below in the experimental section describing the working examples.

All variable groups of these methods are as described in the generic description if they are not specifically defined below. When a variable group or substituent with a given symbol (i.e. G, G′, M) is used more than once in a given structure, it is to be understood that each of these groups or substituents may be independently varied within the range of definitions for that symbol.
Within these general methods the variable Z is equivalent to the moiety
in which each variable group or substituent is allowed to vary independently within the limits defined for that symbol.
Within these general methods the variable E is equivalent to the moiety
in which each variable group or substituent is allowed to vary independently within the limits defined for that symbol.
It is recognized that compounds of the invention with each claimed optional functional group cannot be prepared with each of the below-listed methods. Within the scope of each method optional substituents are used which are stable to the reaction conditions, or the functional groups which may participate in the reactions are present in protected form where necessary, and the removal of such protective groups is completed at appropriate stages by methods well known to those skilled in the art.
Additional compounds of formula (I) may be prepared from other formula (I) compounds by elaboration of functional groups present. Such elaboration includes, but is not limited to, hydrolysis, reduction, oxidation, alkylation, acylation, esterification, amidation and dehydration reactions. Such transformations may in some instances require the use of protecting groups by the methods disclosed in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis; Wiley: New York, (1999), and incorporated herein by reference. Such methods would be initiated after synthesis of the desired compound or at another place in the synthetic route that would be readily apparent to one skilled in the art.
General Method A—Invention compounds of formula 5 in which Z and E are as defined above, may be conveniently prepared according to a reaction sequence as shown in General Method “A”. Thus, amidine or guanidine 1 and β-ketoester 2 are either obtained from commercial sources or made by one skilled in the art according to published procedures (amidine 1: Granik et al Russ Chem. Rev. 1983, 52, 377-393; β-ketoester 2: Tabuchi, H. et al. Synlett 1993, (9), 651-2). Amidine or guanidine 1 is treated with β-ketoester 2 in a refluxing mixed solvent such as alcohol and toluene or benzene to furnish pyrimidinone intermediate 3. The alcohol is typically a lower molecular weight alcohol such as ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, or t-butanol. Compound 3 is treated with a chlorinating agent such as phosphorous oxychloride, thionyl chloride or phosphorous pentachloride to yield chloropyrimidine intermediate 4. Intermediate 4 is reacted with a nucleophile of formula NHR1Z in a refluxing solvent such as alcohol, water, DMF, DMA, acetonitrile, acetone, dioxane or DMSO to furnish the invention compound of formula 5 [formula (I), where R2a is H]. Such reactions can also be done in a melt free of solvent or in a solvent catalyzed by acids such as HCl, H2SO4 or bases such as but not limited to triethylamine, Cs2CO3, K2CO3, Na2CO3, K3PO4, Na3PO4, NaOH, KOH, NaH, NaNH2, KNH2, or a sodium or potassium alkoxide or 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU). Invention compounds of formula 5a [(I) where R2a is Cl, Br or I] can be prepared from compounds of formula 5 by halogenation with Cl2, Br2, or I2. Invention compounds of formula 5a [(I) where R2a is F] can be prepared from the formula (I) compounds where R2a is Cl, Br or I by a nucleophilic substitution reaction using a fluoride source, e.g., KF.

General Method B—Compounds of formula 5 in which R1, R2, Z and E are as previously defined can also be prepared via an alternative reaction sequence outlined in General Method “B” below. Thus, dichloropyrimidine 8, which is either commercially available or can be made by one skilled in the art according to published procedures (Bagli, J. et al, J. Med. Chem. 1988, 31(4), 814-23), is reacted with a nucleophile of formula NHR1Z in a solvent such as alcohol, water, DMF or DMSO to furnish intermediate 9. Such condensations can also be done in a solvent catalyzed by acids such as HCl, H2SO4 or an aforementioned base. Compound 9 is reacted with a boronic acid or ester of formula E-B(OR′)2 where R′ is H, alkyl or two R′ may form a ring, under standard Suzuki coupling conditions (such as Pd(PPh3)4 or PdCl2(dppf).CH2Cl2/base/solvent) to provide invention compound 5.

General Method C—Invention compounds of formula 5 in which R1, R2 and E are as defined above, and Z, L′ are defined below can also be prepared via an alternative reaction sequence outlined in General Method “C” below. Thus, intermediate 4 is reacted with a nucleophile of formula 6 using aforementioned conditions (General Method A) to furnish intermediate 10. Compound 10 is treated with an aromatic intermediate of formula 7 in an aprotic solvent and base (such as bases in General Method A) to furnish invention compounds of formula 5.

General Method D—Invention compounds of formula 13 in which R1, R2 and Z are as defined above, and RD is G2, G12, G23, G24, G30, or benzyl can also be prepared via a reaction sequence as shown in General Method “D” below. Thus, demethylation of intermediate 11 (General method A or B or C) employing standard conditions (such as BBr3, Me3SiI, AlCl3/EtSH etc.) provides intermediate 12. Subsequently, compound 12 can then undergo alkylation, acylation, or sulfamylation to introduce the RD substituent and provide the compound of formula 13. Standard reaction conditions for these transformations can be used, i.e., a reagent of formula RD-halo in the presence a base. In addition, O-alkylation can be accomplished using a Mitsunobu reaction (i.e., DEAD/PPh3) to provide invention compound 13 where RD is alkyl.

General Method E—Invention compounds of formula 16 and 17 in which R1, R2, G, G″, m, n, and E are as defined above, and M′ is CH or N, can be prepared via a reaction sequence as shown in General Method “E” below. Thus, the cyano group of intermediate 14 can be hydrolyzed and the resulting carboxylic acid can be coupled with an amine such as NHR28R29, a piperdine, or morpholine, under standard conditions to provide compound 16 where GE−1 is G21, G25 or G26. Invention compound 17 can be prepared by reduction of the amide 16 with LiAlH4 or BH3, followed by optional sulfonylation or acylation. Alternatively, compound 17 can be prepared by alkylation or reductive amination of amine 15, which is prepared by reduction of 14 by a reducing agent such as H2/Pd on C in acetic acid.

General Method F—Invention compounds of formula 17b can be prepared by displacement of the halo substituent on the compound of formula 17a with a sulfur, nitrogen or oxygen nucleophile, represented by GF-1-H, e.g., a thiol, ammonia, a mono or dialkylamine, water or an optionally substituted alcohol, in the optional presence of a base such as triethylamine, Cs2CO3, K2CO3, Na2CO3, K3PO4, Na3PO4, NaOH, KOH, NaH, NaNH2, KNH2, or a sodium or potassium alkoxide or 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU). Thus are prepared compounds of formula (I) in which GF−1 is selected from G2, G3, G8, G16, G17, G22, G23, and G24. In addition, compounds of formula 17c may be prepared by acylation or sulfonylation of the compounds of formula 17b where at least one H may be replaced, using appropriate reagents such as acyl halides or alkylsulfonyl halides, generally in the presence of a base. Thus are prepared compounds of formula (I) in which GF−2 is selected from G12, G29, G30 and G31.
General Methods (a-e) for Preparation of Intermediate NHR1Z
Method a—The compounds of formula 18 in which M, G, G″, m and n are as defined above, M′ is independently CH or N, and L′ is O or NR5 can be conveniently prepared as shown in Method a below. Generally, the intermediate 18 may be prepared by an aromatic substitution reaction of intermediate 7 and intermediate 6. Thus, aniline or aminopyridine 6 is treated with an aromatic intermediate of formula 7 in an aprotic solvent such as DMF, DMA, acetonitrile, acetone, dioxane or DMSO and base to furnish the intermediate of formula 18 (when X=OTf, OMs, OTs see ref. Sammes, P. et al. J. Chem. Soc. Perkin Trans 1, 1988, (12), 3229-31). Compounds of formula 18a can be obtained through reductive amination of 18 with an aldehyde under reductive amination conditions such as NaBH4, NaBH3CN, or NaBH(OAc)3.

Method b—Alternatively, compounds of formula 18b, in which M, G, G″, m and n are as defined above, M′ is independently CH or N, and L′ is O, NR5 or CH2, can be conveniently prepared as shown in Method b below. Thus, the aromatic intermediate of formula 20 is deprotonated with an aforementioned base or LDA, n-BuLi, t-BuLi in an aprotic solvent, followed by reaction with intermediate 19 to furnish the intermediate of formula 21. The nitro group of compound 21 can be reduced by one skilled in the art according to published procedures such as catalytic hydrogenation, Fe/HOAc and SnCl2 to provide intermediate 18b.

Method c The 4-substituted aniline compound of formula 25, 26 and 27 in which G, G″, m and n are as defined above, P′ is a protecting group, M′ is independently CH or N, and R6 is H or (C1-C3)alkyl can be prepared via a reaction sequence as outlined in Method c below. Thus, intermediate 22 is treated with acyl chloride 23 under Friedel-Crafts acylation conditions (Lewis acid such as AlCl3) to furnish the intermediate of formula 24. Compound 24 can be converted to aniline 25 by Grignard reaction with R6MgBr or reduction with LiAlH4 followed by deprotection. Aniline 26 can be obtained by reduction of the carbonyl group of 24 by methods such as but not limited to N2H4/OH−, Pd/C/H2, Et3SiH/Lewis acid, or NaBH4/Lewis acid (see ref Ono, A. et al, Synthesis, 1987, (8), 736-8) or alternatively by formation of a dithiane and subsequent desulfuration with Raney Nickel. In some instances, deprotection of aniline may be necessary to obtain 26. By deprotection of the amino group of compound 24, the aniline intermediate 27 can also be obtained.

Method d The 3-substituted aniline compounds 30, 30a and 31 in which G, G″, m and n are as defined above, M′ is independently CH or N, and R6 is H or (C1-C3)alkyl can be prepared conveniently via a reaction sequence as shown in Method d below. Thus, nitration of intermediate 28 employing standard nitration conditions such as but not limited to HNO3/H2SO4, or NaNO3/HCl furnishes intermediate 29. Reduction of 29 with a reducing agent such as SnCl2, Fe/HOAc, or catalytic hydrogenation provides aniline 30. Additionally, compound 29 can be converted to aniline 30a by treatment with R6MgBr or reduction with LiAlH4 followed by the above-mentioned reduction conditions. Aniline 31 can be obtained by reduction of the carbonyl group by a method such as but not limited to N2H4NaOH, Pd—C/H2, Et3SiH/Lewis acid, or NaBH/Lewis acid (see ref. Ono, A. et al, Synthesis, 1987,
(8), 736-8) or alternatively by formation of dithiane and subsequent desulfuration with Raney Nickel. In some instances, reduction of the nitro group by an aforementioned method may be necessary to obtain aniline 31.

Method e The compounds of formula 36 and 37 in which M, G, G″, m, n, R10 and R11 are as defined above and Re is G2, G16, G23, and G24, can be prepared conveniently via a reaction sequence as shown in Method e below. Thus, intermediate pyridine 32 is oxidized by a reagent such as m-CPBA, H2O2, CH3C(O)OOH, or CF3C(O)OOH to the N-oxide, followed by chlorination with a chlorinating agent such as phosphorous oxychloride, thionyl chloride or phosphorous pentachloride to yield chloropyridine 33. Compound 33 can be converted to aniline 36 by treatment with alcohol in the presence of base such as NaH, followed by reduction of the nitro group with a reducing agent such as SnCl2, Fe/H+, or catalytic hydrogenation. Treatment of compound 33 with amine HNR10R11 followed by reduction of the nitro group of resulting compound 34 with the above mentioned reagents provides compound 37.

By using these above described methods, the compounds of the invention may be prepared. The following specific examples are presented to further illustrate the invention described herein, but they should not be construed as limiting the scope of the invention in any way.
Abbreviations and Acronyms
A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87.
More specifically, when the following abbreviations are used throughout this disclosure, they have the following meaning:
2×two times3×three timesAlMe3trimethylaluminumBoct-butoxycarbonyln-BuLibutyllithiumt-BuOKpotassium t-butoxidecalcdcalculatedCelite ®diatomaceous earth filtering agent, registeredtrademark of Celite Corp.CD3ODmethanol-d4CHCl3-dchloroform-dddoubletDBU1,8-diazobicyclo[5.4.0]undec-7-eneDCCdicyclohexylcarbodiimideDEADdiethylazodicarboxylateDIBAHdiisobutylaluminum hydrideDIEAdiisopropylethylamineDMAdimethylacetamideDMAP4-dimethylaminopyridineDMEdimethoxyethaneDMFN,N-dimethylformamideDMSOdimethylsulfoxideDMSO-d6dimethylsulfoxide-d6EDCI1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochlorideEtSHethanethiolEtOAcethyl acetateEtOHethanolEt3SiHtriethylsilanehhour(s)HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium hexafluorophosphateHexhexanes1H.NMRproton nuclear magnetic resonanceHOAcacetic acidHPLChigh performance liquid chromatographyLC-MSliquid chromatography/mass spectroscopyLDAlithium diisopropylamideLiHMDSlithium hexamethyldisilazidemmultipletm-CPBA3-chloroperoxybenzoic acidMeOHmethanolminminute(s)Me3SiItrimethylsilyl iodideMS ESmass spectroscopy with electrosprayNaBH(OAc)3sodium triacetoxyborohydrideOMsO-methanesulfonyl (mesylate)OTsO-p-toluenesulfononyl (tosyl)OTfO-trifluoroacetyl (triflyl)Pd/Cpalladium on carbonPd2(dba)3tris(dibenzylideneacetone)dipalladium(0)Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0)PdCl2(dppf)•CH2Cl2[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complex with dichloromethaneRTretention timertroom temperatureRfTLC Retention factorssingletttripletTFAtrifluoroacetic acidTHFtetrahydrofuranTLCthin layer chromatographyGeneral Analytical Procedures
The structure of representative compounds of this invention were confirmed using the following procedures.
Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard 5890 Gas Chromatograph with a J & W DB-5 column (0.25 uM coating; 30 m×0.25 mm). The ion source was maintained at 250° C. and spectra were scanned from 50-800 amu at 2 sec per scan.
High pressure liquid chromatography-electrospray mass spectra (LC-MS) were obtained using either a:
(A) Hewlett-packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2×23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 min at a flowrate of 1.0 mL/min is used with an initial hold of 0.5 min and a final hold at 95% B of 0.5 min. Total run time is 6.5 min.
or
(B) Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215 Autosampler, a Gilson diode array detector, a YMC Pro C-18 column (2×23 mm, 120 A), and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. Spectra were scanned from 120-800 amu over 1.5 seconds. ELSD (Evaporative Light Scattering Detector) data is also acquired as an analog channel. The eluents were either A: 2% acetonitrile in water with 0.02% TFA or B: 2% water in acetonitrile with 0.018% TFA. Gradient elution from 10% B to 90% over 3.5 min at a flowrate of 1.5 mL/min is used with an initial hold of 0.5 min and a final hold at 90% B of 0.5 min. Total run time is 4.8 min. An extra switching valve is used for column switching and regeneration.
Routine one-dimensional NMR spectroscopy is performed on 400 MHz Varian Mercury-plus spectrometers. The samples were dissolved in deuterated solvents obtained from Cambridge Isotope Labs, and transferred to 5 mm ID Wilmad NMR tubes. The spectra were acquired at 293 K. The chemical shifts were recorded on the ppm scale and were referenced to the appropriate solvent signals, such as 2.49 ppm for DMSO-d6, 1.93 ppm for CD3CN-d3, 3.30 ppm for CD3OD 5.32 ppm for CD2Cl2-d2 and 7.26 ppm for CHCl3-d for 1H spectra.
General HPLC Purification Method
Preparative reversed-phase HPLC chromatography was accomplished using a Gilson 215 system, typically using a YMC Pro-C18 AS-342 (150×20 mm I.D.) column. Typically, the mobile phase used was a mixture of (A) H2O containing 0.1% TFA, and (B) acetonitrile. A typical gradient was:
Time [min]A: %B: %Flow [mL/min]0.5090.010.01.011.000.0100.01.014.000.0100.01.015.02100.00.01.0